Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients

Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR-and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLC gamma 2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral bloo

Epidermal Growth Factor Receptor-Targeted Gelatin-Based Engineered Nanocarriers for DNA Delivery and Transfection in Human Pancreatic Cancer Cells

Type B gelatin-based engineered nanocarrier systems (GENS) have been used over the last several years as a non-condensing systemic and oral DNA delivery system. In this study, we have modified the surface of GENS with epidermal growth factor receptor (EGFR)-targeting peptide for gene delivery and transfection in pancreatic cancer cell lines. GENS were prepared by the solvent displacement method and the EGFR-targeting peptide was grafted on the surface using a hetero-bifunctional poly(ethylene glycol) (PEG) spacer. Plasmid DNA, encoding for enhanced green fluorescent protein (GFP), was efficiently encapsulated and protected from degrading enzymes in the control and surface-modified GENS. Upon incubation with EGFR over-expressing Panc-1 human pancreatic adenocarcinoma cells, the peptide-modified nanoparticles were found to be internalized efficiently by receptor-mediated endocytosis. Both quantitative and qualitative transgene expression efficiencies were significantly enhanced when plasmid DNA was administered with EGFR-targeted GENS relative to the control-unmodified gelatin or PEG-modified gelatin nanoparticle systems. Based on these preliminary results, EGFR-targeted GENS show tremendous promise as a safe and effective gene delivery vector with the potential to treat pancreatic cancer